P683: A FIRST-IN-HUMAN PHASE 1 STUDY OF ORAL LOXO-338, A SELECTIVE BCL2 INHIBITOR, IN PATIENTS WITH ADVANCED HEMATOLOGIC MALIGNANCIES (TRIAL IN PROGRESS)
Authors: W. Jurczak, A. J. Alencar, G. S. Guru Murthy, M. Hoffmann, J. M. Pagel, V. Patel, J. M. Pauff, P. L. Zinzani, S. Le Gouill, A. R. Mato, L. E. Roeker
Journal: HemaSphere (2022)

Background: B-cell lymphoma 2 (BCL2) is a key regulator of apoptosis and provides protection from cell death in many hematological malignancies. LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2, designed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition. In preclinical studies, LOXO-338 showed a favorable pharmacological profile, selectively inhibited BCL2, and was well-tolerated in vivo. LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor (Brandhuber et al. Cancer Res 2021;81,13 Suppl:1258). Aims: To determine the recommended phase 2 dose of LOXO-338 and evaluate the safety profile of LOXO-338 as monotherapy and in combination. Methods: LOXO-BCL-20001 is a global, open-label, multi-center, first-in-human phase 1 study of oral LOXO-338 in patients with advanced hematologic malignancies who have received standard therapy (NCT05024045). The study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy, and will explore different dosing strategies. Part 2 will evaluate LOXO-338 in combination with pirtobrutinib. Part 1 dose escalation portion of the study will follow an i3 + 3 design. Each cycle will be 28 days (4 weeks). Eligible patients include those with CLL/SLL, mantle cell lymphoma, and Waldenstrӧm macroglobulinemia (WM) who received standard therapy. Patients with other B-cell non-Hodgkin lymphomas (NHL) who failed standard therapy or, in the opinion of the investigator, have no known available options to provide benefit for the patient’s condition, are also eligible. Patients must have recovered from prior treatment-related adverse events. Patients with active or suspected Richter transformation, transformed low grade lymphoma, Burkitt or Burkitt-like lymphoma, and multiple myeloma are also eligible. Patients with AL amyloidosis are eligible in monotherapy dose expansion; all other patients are eligible in both monotherapy and combination dose expansion. Patients must not have progressed while receiving prior BCL2 inhibitor; those with WM or AL amyloidosis must not have received a prior BCL2 inhibitor. Key exclusion criteria include history of CNS involvement, stem cell transplant or CAR-T therapy <60 days, concurrent anticancer therapy, and clinically significant cardiovascular disease. The primary objective of part 1 is to determine the recommended phase 2 dose of oral LOXO-338 in patients who were previously treated for CLL/SLL and other B-cell NHL, administered alone or in combination with pirtobrutinib. Determining antitumor activity in patients with WM and AL amyloidosis is an additional primary objective of part 1 monotherapy. Secondary objectives include determining the safety profile and tolerability, PK properties and antitumor activity of LOXO-338 in combination with pirtobrutinib. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) based on disease-specific response criteria per investigator assessment. Results: N/A Summary/Conclusion: N/A